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Mol Pharm. 2017 Dec 4;14(12):4551-4559. doi: 10.1021/acs.molpharmaceut.7b00669. Epub 2017 Nov 7.

Delayed Sequential Co-Delivery of Gefitinib and Doxorubicin for Targeted Combination Chemotherapy.

Author information

1
Chemical Engineering Program, Department of Chemical and Environmental Engineering, University of Cincinnati , Cincinnati, Ohio 45221-0012, United States.
2
Department of Cancer Biology, College of Medicine University of Cincinnati , Cincinnati, Ohio 45267-0521, United States.
3
Research Service, Cincinnati Veteran Hospital Medical Center , Cincinnati, Ohio 45267-0521, United States.

Abstract

There are an increasing number of studies showing the order of drug presentation plays a critical role in achieving optimal combination therapy. Here, a nanoparticle design is presented using ion pairing and drug-polymer conjugate for the sequential delivery of gefitinib (Gi) and doxorubicin (Dox) targeting epidermal growth factor receptor (EGFR) signaling applicable for the treatment of triple negative breast cancers. To realize this nanoparticle design, Gi complexed with dioleoyl phosphatidic acid (DOPA) via ion paring was loaded onto the nanoparticle made of Dox-conjugated poly(l-lactide)-block-polyethylene glycol (PLA-b-PEG) and with an encapsulation efficiency of ∼90%. The nanoparticle system exhibited a desired sequential release of Gi followed by Dox, as verified through release and cellular uptake studies. The nanoparticle system demonstrated approximate 4-fold and 3-fold increases in anticancer efficacy compared to a control group of Dox-PLA-PEG conjugate against MDA-MB-468 and A549 cell lines in terms of half maximal inhibitory concentration (IC50), respectively. High tumor accumulation of the nanoparticle system was also substantiated for potential in vivo applicability by noninvasive fluorescent imaging.

KEYWORDS:

EGFR inhibitor; combination therapy; controlled delivery; doxorubicin; nanoparticles; sequential delivery

PMID:
29077410
PMCID:
PMC5714665
DOI:
10.1021/acs.molpharmaceut.7b00669
[Indexed for MEDLINE]
Free PMC Article

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